The present disclosure is broadly concerned with automated papanicolaou (Pap) screening technology.
Cervical cancer is the leading cause of death of women in third world countries. In the U.S., approximately 13,000 women were diagnosed with cervical cancer in the year 2002 alone. The Pap test is used to screen for cervical cancer, and is generally considered to be the most effective screening technique ever developed for any cancer. Current medical practice calls for each female above adolescence to receive one Pap test annually. This amounts to approximately 50 million tests a year in the U.S., and approximately 60 million abroad.
Of the tests done each year in the U.S., approximately 7% display abnormalities that require additional clinical follow-up. A substantially greater percentage reveal other abnormalities that do not necessarily represent precancerous changes, such as low grade squamous intraepithelial lesions (LSIL) and atypical squamous cells of undetermined significance (ASCUS), but may nonetheless assume importance in risk stratification.
Of the nearly one hundred strains of Human Papilloma Virus (HPV) that have been identified to date, a small subset has been recognized as high-risk, with a strong correlation to development of precancerous changes of the cervix known as high grade squamous inter-epithelial lesions (HSIL). Indeed, infection with a high-risk HPV constitutes the major risk factor for development of cervical cancer.
The conventional approach to Pap screening is not able to detect infection with high-grade HPV, nor is it able to distinguish reliably between ASCUS and HSIL. In response to this deficiency of conventional microscopy, the National Cancer Institute sponsored a multicenter ASCUS/LSIL Triage Study (ALTS) to determine optimum strategies for early detection of women at risk of developing cervical cancer. The triage study tested three follow up procedures: immediate colposcopy, HPV testing, and conservative management with repeating of the Pap smear examination. The trial results concluded that HPV testing is a preferred option in the management of women with ASCUS because of its sensitivity and specificity as a disease marker.
In the ALTS study, HPV was detected utilizing a hybrid capture method (Digene Corporation) in which residual fluid from liquid-based Pap smear specimens is placed into a microwell plate, and the presence of selected HPV strains produces chemiluminescence. Microscopic visualization of the infected cells in the specimen is not possible. Immunohistochemical staining is an alternative approach that has been used for HPV detection. This approach allows the pathologist to visualize the infected cells, however sensitivity and specificity is reduced in comparison to the hybrid capture method. In addition, the colorimetric appearance of the sample is quite different from the customary Pap smear.
Because in the United States approximately 50 million women undergo Pap testing to screen for the presence of cancer or high-risk precursor lesions, examination of this enormous number of slides requires a suitably large number of well-trained cytotechnologists. Unfortunately, the availability of competent cytotechnologists is decreasing. Additionally, each slide to be examined by the cytotechnologist contains 200,000 to 500,000 cells, which must ideally all be checked. The repetitive nature of this job makes it difficult to prevent decay in attentiveness and performance towards the end of the workday. As a result, there has been an effort to develop automated Pap screening technology to augment the decreasing number of competent cytotechnologists as well as to enhance the consistency of the screening and throughput of all of the slides.
Because a given Pap smear is often viewed quite differently by different pathologists, as clearly reflected in the structure of the Bethesda classification system, the need for a rigorous method of quantifying diagnostic criteria has long been recognized in this profession. Automated Pap screening that relies on computer-based algorithms has the potential for addressing this problem.
Presently, there is one fully automated screening system that has received FDA approval, namely, TriPath Imaging, of Burlington, N.C. Although numerous studies of the TriPath system have appeared in professional literature, the bulk of these studies have concentrated on assessing the sensitivity of this automated instrument. Performance of the TriPath system has been acceptable in this respect. However, the specificity of the TriPath system has not produced nearly as acceptable results. In its FDA approval usage, the TriPath system can “sign-off” on a maximum of 25% of the slides it reviews as requiring no further review. While this may provide modest time savings for a high-volume pathology laboratory, given that 90-95% of the slides screened in a typical laboratory are truly normal, the ability to sign off on only 25% falls far short from what is needed by an automated system.
The TriPath system uses straightforward morphological criteria for assessing cells that are potentially problematic, choosing those cells whose nuclei are deemed to be unusually large and optically dense. These computational algorithms are not capable of accurate, reliable results when confronted with the frequent occurrence of uneven staining and overlapping clumps of cells.